Pyrrolobenzodiazepines and conjugates thereof

Abstract

Conjugate compounds of formula (A):wherein:R2 iswhere R36a and R36b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester or, when one of R36a and R36b is H, the other is selected from nitrile and a C1-4 alkyl ester;R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;Y is selected from formulae A1, A2, A3, A4, A5 and A6:L is a linker connected to a cell binding agent;CBA is the cell binding agent;n is an integer selected in the range of 0 to 48;RA4 is a C1-6 alkylene group;either(a) R10 is H, and R11 is OH, ORA, where RA is C1-4 alkyl; or(b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(c) R10 is H and R11 is OSOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;R and R′ are each independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;wherein R16, R17, R19, R20, R21 and R22 are as defined for R6, R7, R9, R10, R11 and R2 respectively;wherein Z is CH or N;wherein T and T′ are independently selected from a single bond or a C1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; andX and X′ are independently selected from O, S and N(H).

Description

[0001]The present invention relates to pyrrolobenzodiazepines (PBDs), in particular pyrrolobenzodiazepines having a linker group connected to a cell binding agent.BACKGROUND TO THE INVENTIONPyrrolobenzodiazepines[0002]Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994); Antonow, D. and Thurston, D. E., Chem. Rev. 2011 111 (4), 2815-2864). Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Paten...

AI Technical Summary

Benefits of technology

The present invention provides novel compounds that can be used to connect a cell binding agent to a drug or other molecule. These compounds have a linker with a triazole, piperazine, propargylene, or oxime group attached to a phenylene or pyridylene dimer. The linker can be connected to the cell binding agent through a triazole, piperazine, or propargylene group. The compounds have specific structures and can be used to treat medical conditions. The invention also provides methods for preparing the compounds and pharmaceutical compositions containing them.

Problems solved by technology

The use of antibody-drug conjugates (ADC), i.e. immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumor cells in the treatment of cancer, targets delivery of the drug moiety to tumors, and intracellular accumulation therein, whereas systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Xie et al (2006) Expert. Opin. Biol. Ther.

Images